1. Field of Invention
This invention relates to a device for scanning, detecting and controlling directed beams of laser light, and more particularly to a device for scanning concurrently two beams of laser light across an area to be treated by one of said light beams (the "treating beam") while the second of said beams (the "analysis beam") detects the properties of the scanned area and controls the intensity and certain other properties of the treating beam so as to provide continuous optimal treatment despite variations in the properties of the scanned area.
2. Summary of Technical Background
There are at least three characteristics of laser light which have led to the increasing importance of lasers in science, engineering and medicine. These characteristics are: (1) Lasers typically produce light having a very precise wavelength. Thus, such light is capable of exciting very well-defined atomic and molecular transitions in specific substances, leading to the possibility of accurate detection and analysis. (2) Monochromatic and coherent laser light is capable of being focused to a very small spot. This leads to the possibility of accurate spacia resolution. (3) Laser light can be produced in focused or diffuse spots with considerable power density, thus leading to the possibility of beneficial processing of the target substance solely by means of laser light.
The invention described herein uses all three characteristics of laser light. In order to be concrete, our discussion will emphasize the problems associated with lasers as tools for medical diagnosis and treatment. However, the invention described herein is simply adaptable to any problem requiring a continuous analysis and laser treatment of a region with nonuniform characteristics. Such problems may occur in laser processing of metals, alloys, ceramics, plastics or other materials in which, due to prior processing or inherent properties, the optimal laser processing parameters vary over the region. The modification of the apparatus described herein to handle such nonmedical problems would be obvious to anyone having ordinary skills.
Lasers in medicine have been used in many applications, both with relatively low powers of laser light as a diagnostic technique, and with relatively high powers as a method of treatment. For example, in general surgery lasers have been used for the cutting of tissues, selective biostimulation and coagulation of bleeding, nonhealing and suppurative wounds and ulcers. In physiotherapy lasers have been used for irradiation of inflamed areas of skin, mucosa, joints, reflexogenic zones and acupuncture points. Typically in such applications treatment is usually performed by a helium-neon ("He-Ne") laser (emitting light with a wavelength of typically 633 nanometers, "nm") or with a diode laser (emitting typically in the region 800 to 900 nm). Typically, He-Ne lasers are used in such applications to deliver power in the range 1-30 milliwatts ("mW"), while the diode lasers will typically be used to deliver 1-5 mW. Treatment is typically performed by delivery of the light either through flexible optical fibers or by manipulation of mirrors. When stimulating the regeneration of large, injured inflamed areas or stimulating the response from reflexogenic zones, the laser beam is typically dispersed by means of a lens having a relatively short focal length to cover the whole (or at least an expanded region) of the target area requiring treatment. Typically, the targets treated by this method will be from 1 to 15 cm in diameter and require 0.1 to 3.0 mW/(cm.sup.2) of laser power delivered to the target. Diode lasers are occasionally used in a modulated mode depending on the treatment purposes.
A common problem in the treatments described above is the need to treat an area with laser light in which, typically, different parts of the total area to be treated will require different levels of exposure to laser light. The consequences of overexposure may be very severe (as in the removal of arterial plaque described below), or not serious enough to cause concern. The problem addressed by the present invention is to regulate and to deliver the therapeutic dosage of laser light to every point requiring treatment, while reducing overexposure of any area.
Lasers have also been used in dermatology and cosmetology for photothermal evaporation or photochemical decolorization of portwine stains, birthmarks, freckles, tattoos, etc. The photothermal evaporation and photochemical decolorization of hyperpigmented areas are typically performed by means of a carbon dioxide laser (emitting typically at a wavelength near 10,600 nm), or an argon laser (emitting typically 488 nm and 514 nm). Treatment powers typically in the range 3-50 watts ("W") are employed using either a fiber optical beam delivery or a system of hard mirrors depending on the characteristics of the laser (that is, the ability of present optical fibers to transmit that wavelength light at the required power level).
Carbon dioxide and argon lasers are also typically used for the cauterization of bleeding capillaries and larger blood vessels, and to coagulate suppurative and necrotic tissues of abscesses, wounds, or ulcers, and for evaporation and decolorization. For such applications, the distal tip of the light delivery system is typically moved by the surgeon by hand in an attempt to irradiate uniformly all points of the pathological area. In such procedures, typically the distance between the distal tip of the light delivery system is varied by the surgeon to adjust the power density (W/cm.sup.2) delivered to the pathological area. The length of time the surgeon exposes each area, multiplied by the delivered power density, determines the total exposure to light, measured typically in Joules ("J")/(cm.sup.2). The experience and intuition of the surgeon determines the exposure delivered at each point of the region, which can easily result in under- or overexposures for even the most expert surgeons. It is a major purpose of the present invention to provide the surgeon with more quantitative data about the region to be treated and, in appropriate cases, to automate the scanning, analysis and treatment procedures.
A very important new application for laser surgery is in the field of cardiology, removing arterial obstructions by means of laser light delivered through an optical fiber. The use of laser surgery in this manner removes the need to open the chest and interrupt blood flow for the duration of the surgical procedure (an advantage, also, in surgery in the abdomen and other body cavities). A major impediment to full clinical application of such surgery is the possibility that the surgeon will not be able to tell obstructing plaque from the wall of the blood vessel itself. Thus, inadvertent puncture of the wall of a major blood vessel is very possible: a very serious problem as the vessel is not immediately accessible to the surgeon for repair.
A recent advance in this area has been the work of F. W. Cutruzzola et. al. ("Change in Laser-Induced Arterial Fluorescence During Ablation of Atherosclerotic Plaque", Lasers Surg. Med. Vol 9, No. 2, pp. 109-116, 1989). In this work on human cadaver aorta, it was found that laser-induced florescence spectroscopy is capable of discriminating atherosclerotic regions from normal aorta. Thus, the possibility is present to let the surgeon analyze "on the fly" the region of aorta to be laser-ablated just prior to such ablation. Equally important, continuous analysis by laser spectroscopy will tell the surgeon when ablation has proceeded far enough, and only normal aorta remains. This is the surgeon's signal that no further ablation of that particular region is needed and attention should be turned elsewhere before puncture of the aorta wall occurs. Extensive use of this technique has been demonstrated by Kittrell et al in U.S. Pat. No. 4,718,417.
Thus, for the removal of aorta plaque it has been demonstrated that laser analysis of the region to be treated, as well as laser treatment may both be necessary for effective surgery. The invention described herein consists of apparatus for assisting the laser surgeon in performing such analysis and treatments in a variety of surgical and medical applications.
The invention described herein relates to an apparatus for the automatic adjustment of power and properties the treating laser beam in accordance with information obtained by means of a probe or analyzing laser beam. (Fully automated scanning is an optional feature of the invention, appropriate for some applications, but not required for those cases in which the surgeon desires to maintain manual control.) As such, it will have obvious applications to those areas of medicine and surgery described above, and others which will be obvious to practitioners having ordinary skills in those fields. However, a major impetus for the development of this invention is for the photodynamic treatment of cancer. Such photodynamic therapy ("PDT") procedures will be the focus of our discussion and supply the primary examples for the uses of the invention described herein. Such emphasis on PDT is in no way intended to exclude other applications as discussed above.
PDT is based upon the existence of certain chemicals which are selectively retained (or conceivably, selectively absorbed) by cancer cells. It is also known that some of these selectively-retained chemicals cause destruction of the cells in which they reside when exposed to light of sufficient intensity and having the appropriate wavelength. Such selective photosensitization is becoming an accepted cancer treatment in appropriate situations.
The leading photochemical cancer treatment at this time involves the injection into the patient of a hematoporphyrin derivative ("HpD"). This drug permeates the tissues of the patient, but typically dissipates from normal cells in 24-48 hours. HpD is typically retained for a longer time by cancer cells. When exposed to light of sufficient intensity and at the appropriate wavelength, HpD undergoes a chemical reaction leading to the destruction of the cell in which it resides. Thus, appropriate timing of the exposure of the patient to light following the administration of HpD leads to selective destruction of those cancer cells exposed to said light. It is generally thought that the mechanism of photochemical cell death involves the production of the singlet electronic state of molecular oxygen, which attacks vital portions of the cell.
However, it is necessary to exercise care in the exposure of the patient to light following HpD administration. Overexposure of the patient can lead to the unwanted death of normal cells (presumably containing trace amounts of HpD at the time of treatment with light). Underexposure will lead to incomplete destruction of the patients cancer cells, obviously leading to a recurrence of the disease. Thus, surgeons would very much like to be able to monitor the dosage delivered to each point of the affected region and, at the same time, monitor the concentration of photosensitizing chemical (typically, HpD).
Other photosensitizers are currently in various stages of development, experimental and clinical use. These include psoralens, fluorescein, rose bengal, rhodamine 123, various modifications to HpD, Photosan (the tradename of Seehof Laboratory, Federal Republic of Germany), Photofrin (the tradename of QLT Phototherapeutics, Inc., Vancouver, British Columbia, Canada), pheophoride, chlorins, purpurins, phthalocyanines, naphthalocynanines, and others for purposes of diagnosis (typically by fluorescence of the drug) and for photodynamic treatment in the manner of PDT described above.
The choice of necessary laser power and wavelength typically depends upon the extent to which the light beam in question penetrates the natural tissue, by the absorption and fluorescence spectra of the natural pigments and artificial photosensitizers.
For the case of PDT performed with HpD photosentizer, much work has been done on light-induced fluorescence as a means to detect the locations of HpD prior to treatment. Typical (non-laser) excitation is performed by means of a (typically) 200 W mercury lamp, filtered to provide a relatively narrow emission peak near 405 nm. (For example, see D. R. Doiron et. al., "Fluorescence Bronchoscopy for Detection of Lung Cancer", Chest, Vol. 76, PP. 27-32, July 1979). Laser light may also be used, for example a Spectra-Physics Model 164-11/265.RTM. krypton ion laser, capable of emitting 200 mW of power in three closely spaced lines in the violet region of the visible spectrum (406 nm-415 nm). The laser beam is typically focused by a lens onto the core of a suitable optical fiber, typically a nonfluorescing fused quartz fiber with a core approximately 0.40 mm in diameter. (See, for example, E. G. King et. al. "Fluorescence Bronchoscopy in the Localization of Bronchogenic Carcinoma", Cancer, Vol. 49, pp. 777-782, 1982). The resulting red fluorescence is typically collected by means of the objective lens of an endoscope and focused on the photocathode of an image intensifier. Typically, on the way to the image intensifier tube the light is processed by passing through a nonfluorescent red bandpass filter designed to reject the reflected violet light from the exciting laser, as well as to reject most of the fluorescence from normal tissue. In a typical application, the image intensifier consists of a three-stage, electrostatic-focus tube with an overall gain more than 30,000. Thus, a dim red image passing through the endoscope is transformed into a bright green image which can be viewed by the medical team and photographed at the output of the intensifier. A significant disadvantage of this method is the need for continuous adjustment by hand of the endoscopic fiber (or other means employed to deliver the analyzing light) to compensate for movement in the irradiated area. Such movements would typically be most pronounced in the study of contracting or pulsating organs such as the stomach.
Such fluorescence serves as a means to locate the photosensitizers and, hence, locate the diseased cells to be treated. This technique has been in use long before it was realized that light could also serve as the method of treatment, simply using the fluorescence as a means for locating the region for conventional surgical removal. However, the treatment possibilities have expanded considerably with the realization that intense light (typically having a different wavelength from the fluorescence-inducing, or analysis, light) could also lead to the destruction of the diseased cells. For the example of HpD, it is believed that this destruction proceeds by means of the production of singlet oxygen.
The use of a second light source (typically a laser) as the method of treatment is quickly becoming an important medical procedure. HpD has been approved for clinical trials for the in situ production of singlet oxygen and the local destruction of tissues and malignant tumors. (For example, see the work of J. S. McCaughan et. al., "Hematoporphyrin-Derivative and Photoradiation Therapy of Malignant Tumors", Lasers Surg. Med., Vol. 3, pp. 199-209, 1983, and the review article by T. J. Dougherty et. al. "The Structure of the Active Component of Hematoporphyrin Derivative", in Porphyrin Localization and Treatment of Tumors, Eds. D. R. Doiron and C. J. Gomer {Alan R. Liss, Inc., New York, 1984}, pp 301-314). Other photosensitizing drugs are also under very active investigation. For example, DHE/Photofrin has been the subject of a recent U.S. Patent (T. J. Dougherty et. al., U.S. Pat. No. 4,649,151), while photosan has been the subject of recent publications (for example see the review article of R. Sroka et. al. "Comparison of Fluorescing and Photosensitizing Properties of Different Porphyrin-Derivative Preparations", appearing in Light in Biology and Medicine, Vol. 1, R. H. Douglas et. al., eds. {Plenum Publishing Corp., New York, 1988}, pp. 127-132).
The production and delivery of the light necessary to produce singlet oxygen and to destroy the tumor is still the subject of active research. It is important in the choice of a light source to achieve a balance of three considerations. First, it is necessary to use light having a wavelength producing sufficient singlet oxygen to effectively kill the tumor cell. However, the wavelength most effective in cell destruction may not penetrate to the site of the tumor very well. Therefore, the second consideration to be taken into account is to use a wavelength that penetrates through typical tissues and reaches the tumor to be treated with sufficient intensity to have the desired therapeutic results. The third consideration is that there must be available a suitably intense source of light at the desired wavelength to deliver therapeutic intensities to the tumor site. A balance of these three considerations must be obtained to achieve effective medical treatment. For HpD, it is typical to use a wavelength of 630 nm. While this is not the most efficient wavelength for causing the production of singlet oxygen, it efficiently penetrates typical biological tissues.
A commonly used method to produce 630 nm light is to employ the continuous wave ("cw") radiation from an argon laser as the pumping device to pump a dye laser. In typical operation, the argon laser will be used to emit radiation at 488 nm or 514 nm pumping a dye laser (typically Rhodamine B or similar dye) adjusted to emit cw radiation at 630 nm (in the red region of the visible spectrum). An alternative method is to use the pulsed output from a gold vapor laser at a wavelength of 628 nm or copper vapor laser at 511 nm or 578 nm to pump a similar dye laser, similarly adjusted to emit at the wavelength of 630 nm. Occasionally, two-photon excitation of such dyes is obtained by pumping with a Nd:YAG laser.
Other photosensitizers currently under investigation (such as vitamin B12, riboflavin, or the psoralens) are used in conjunction with excitation by means of light from the ultraviolet region of the spectrum. Tetracycline, acriflavine, stilbene 420 are examples of photosensitizers using excitation by blue light. Green/yellow light is typically employed to excite fluorescein or rose bengal photosensitizers, while dark red, and infrared light is commonly used in conjunction with methylene blue, pheophorbide, chlorins, lacteriochlorins purpurins, the phthalocyanines, or the naphthalocynanines photosensitizers. In all of these cases both laser and noncoherent (nonlaser) light sources have been used. However, it is typically much more difficult to achieve therapeutic light intensities at the tumor site if lasers are not used. These difficulties are increased if it is required that the light be delivered to the tumor site through an optical fiber, in which coupling nonlaser light into the fiber core requires focusing to a fine spot.
We wish to draw two conclusions from this summary. First, even for a relatively standard PDT procedure, (HpD excited at 630 nm), there is still room for an improved source of light. Second, many novel photosensitizers are under active development. For each such photosentizer a different optimal light source will generally be required. It will introduce major roadblocks to full medical application if a different light source must be engineered for each photosentizer.
It is an important component of the present invention to introduce a flexible laser system, capable of rapid modification to produce light at numerous different frequencies. The light source of the present invention also has certain advantages in the excitation of HpD at 630 nm. The present system can be based, as one of several possible embodiments, upon electron-beam pumping of a semiconductor laser as, for example, disclosed for TV-imaging purposes in the patent of J. R. Packard et. al. (U.S. Pat. No. 3,757,250, {1973}), described in more detail below.
An important advantage of PDT is the possibility of delivering therapeutic intensities of light to the site of the tumor through a flexible, thin optical fiber. In many cases, this can eliminate the need for major surgery in treating tumors in locations which can be reached through body orifices (such as lung, esophagus, stomach, bladder, colon, rectum, etc). In many other cases, such as brain tumors, the treating light can be delivered by means of a fiber inserted into the tumor through a thin needle, markedly reducing damage to intervening, non-tumorous, tissues which conventional surgery would entail. However, the use of optical fibers requires the surgeon to consider the best way to achieve a uniform cell-killing dosage of light throughout the tumorous region. This must be accomplished in spite of varying tumor extents and depths. Clearly, not killing all cancerous tumor cells will lead to the recurrence of the tumor. However, overexposure of non-tumor cells (in which unavoidable traces of photosentizer will be present), should also be avoided. Simply "flooding" the region of the tumor with excessive amounts of light should be avoided as this can lead to the destruction of non-tumorous cells. In certain locations, such as arterial walls, the resulting punctures could be life-threatening for the patient. In other applications, prudent medical procedure will strive to minimize the destruction of non-cancerous cells. This problem is also the subject of the present invention. To more fully describe the advantages of the present invention, we will first describe some of the procedures of PDT performed through an optical fiber.
For the most widespread therapeutic combination of HpD (Photofrin) in combination with an argon pumped dye laser, a typical optical fiber would be a medical-grade quartz fiber having a core diameter of, typically, 0.4 mm. The light exiting from the optical fiber is typically in the approximate shape of a cone with, typically, a divergence about 20 deg. The fiber is typically passed through the open channel of a flexible endoscope such that the distal end protrudes from the tip of the endoscope. A small microlens may be attached integrally to the distal tip of the fiber. In this way the emerging light can be dispersed over a typical diameter of 10 to 12 mm when the fiber is held 1.0 to 1.5 cm from the surface of the tumor, and still produce sufficient intensity over the dispersed region. The proximal end of the fiber is typically attached to a positioning device, or manually manipulated by the surgeon.
The light from the 630 nm source is typically focused directly onto the proximal end of the optical fiber. Typically the light source consists of an argon-pumped dye laser in which the dye (typically Rhodamine B) is circulated through the resonator cavity to avoid a gradual loss over time of laser power emitted at 630 nm. An argon laser with a typical maximum cw power of 20 W is capable of producing an output of 4 W of 630 nm light from a typical dye laser. The output power delivered by the optical fiber is typically measured by means of an externally-calibrated, continuous-wave power meter (as described more fully by D. A. Cortese and J. H. Kinsey, "Endoscopic Management of Lung Cancer with Hematoporphyrin Derivative Phototherapy", Mayo Clinic Proceedings, Vol. 57, pp. 543-547, Sept. 1982).
As discussed above, it is important for the surgeon to be able to deliver a known dose to each point of the tumor. Since such endoscopic procedures are frequently done under general anaesthetic, it is also important to minimize the time of treatment. This has led to the development of modifications of the distal tip of the delivery optical fiber to produce more useful patters of light emitted from the end of the fiber. For example, the patents issued to J. H. McCaughan (U.S. Pat. Nos. 4,660,925 {1987}, and 4,693,556 {1987}) describe devices constructed on the distal end of optical fibers such that the emitted light emerges in uniform cylindrical or spherical patterns, respectively. Such devices have proven themselves to be particularly in obtaining uniform irradiation of tumors of different shapes and extent localized in the bladder, cervix, esophagus, stomach, lung and other more-or-less cylindrical or spherical cavities. The clear limitations of such devices are that not all such tumors have precise cylindrical or spherical symmetry. Thus, it is very difficult to achieve selective irradiation of such tumors having other than precise cylindrical or spherical shapes without simultaneous radiation of residual photosensitizer in adjacent, noncancerous tissues. Constructing a stencil to shield all but the region of the tumor is one possible solution, but suffers from the disadvantages of requiring prior knowledge of the precise shape of the tumor and must be held in position by the surgeon during the procedure. Both requirements add to the total time of the procedure which must be endured by the patient.
Realistic tumors occurring in patients lack a well-defined geometrical shape, making uniform irradiation of the entire tumor very difficult. A further complication is that, even in regions generally considered "tumor" there will be varying concentrations of photosensitizer. For instance, tumors having different depths of cancerous cells (not uncommon) will appear to the surgeon to have different concentrations of photosensitizer. Thicker tumors will naturally require exposure to more therapeutic light to penetrate and destroy the underlying tumor layers. These complications are virtually impossible to be handled by visual inspection, even by very experienced surgeons. Therefore, it is very important to develop ways in which the surgeon can analyze "on-the-fly" at point to point across the tumor the concentration of photosensitizer and, therefore, the amount of light exposure required for full, yet not overexposed, therapeutic treatment.
One approach to this problem of in situ analysis of the concentration of photosensitizer in and around tumors, is that recently patented by J. G. Parker et. al. (U.S. Pat. No. 4,576,173 {1986}). In this work it was recognized that the effective agent in the destruction of cells is the production of singlet oxygen. Thus, this invention discloses a method for monitoring directly the concentration of singlet oxygen. This is complicated by the fact that singlet oxygen emits in the midst of a broad band of background fluorescence from the surrounding medium. Nevertheless, this patent discloses a method involving chopping of the exciting radiation combined with phase sensitive detection to extract the singlet oxygen signal from the background.
The invention described herein consists of a method and apparatus of analysis for the photosensitizer itself rather than singlet oxygen. This offers the advantage simplified methods of detection to extract the signal from the background. In addition, the present invention describes a method for automatically scanning the treating laser beam (630 nm in the case of PDT using HpD). The present invention describes, in addition, a method for automatically controlling the power and certain other characteristics of the treating laser beam depending on the measured characteristics of the point to be treated as measured by the probe or analysis beam. The point-by-point adjustment of the treating laser beam can be used by the surgeon as an aid to his manual control of the surgeon. Alteratively, for appropriate tumors in suitable locations the fully automatic scanning mode can be employed with the treating laser beam being adjusted by the analysis beam without operator intervention in either beam adjustment or beam location.